IL-6 triggers IL-21 production by human CD4+ T cells to drive STAT3-dependent plasma cell differentiation in B cells

Immunol Cell Biol. 2012 Sep;90(8):802-11. doi: 10.1038/icb.2012.17. Epub 2012 Apr 10.


Interleukin (IL)-21-producing CD4(+)T cells are central to humoral immunity. Deciphering the signals that induce IL-21 production in CD4(+) T cells and those triggered by IL-21 in B cells are, therefore, of importance for understanding the generation of antibody (Ab) responses. Here, we show that IL-6 increased IL-21 production by human CD4(+) T cells, particularly in those that express the transcriptional regulator B cell lymphoma (BCL)6, which is required in mice for the development of C-X-C chemokine receptor type 5 (CXCR5(+)) IL-21-producing T follicular helper (T(FH)) cells. However, retroviral overexpression of BCL6 in total human CD4(+) T cells only transiently increased CXCR5, the canonical T(FH)-defining surface marker. We show here that IL-21 was required for the induction of Ab production by IL-6. In IL-21-treated B cells, signal transducer and activator of transcription (STAT)3 was required for optimal immunoglobulin production and upregulation of PR domain containing 1 (PRDM1(+)), the master plasma cell factor. These results, therefore, demonstrate the critical importance of STAT3 activation in B cells during IL-21-driven humoral immunity and suggest that BCL6 expression, although not sufficient, may serve as a platform for the acquisition of a T(FH)-like phenotype by human CD4(+) T cells.

Publication types

  • Research Support, N.I.H., Extramural

MeSH terms

  • Animals
  • Biomarkers / metabolism
  • CD4-Positive T-Lymphocytes / drug effects
  • CD4-Positive T-Lymphocytes / immunology*
  • Cell Differentiation / drug effects
  • Cell Differentiation / immunology*
  • DNA-Binding Proteins / metabolism
  • Humans
  • Immunoglobulins / biosynthesis
  • Interleukin-6 / pharmacology*
  • Interleukins / biosynthesis*
  • Mice
  • Plasma Cells / cytology*
  • Plasma Cells / drug effects
  • Plasma Cells / immunology
  • Proto-Oncogene Proteins c-bcl-6
  • STAT3 Transcription Factor / metabolism*


  • BCL6 protein, human
  • Biomarkers
  • DNA-Binding Proteins
  • Immunoglobulins
  • Interleukin-6
  • Interleukins
  • Proto-Oncogene Proteins c-bcl-6
  • STAT3 Transcription Factor
  • STAT3 protein, human
  • interleukin-21